An unbiased and efficient computerised tomography method to quantify muscle and adipose tissue volume in neuromuscular patients.

The objective was to evaluate the applicability and reliability of an unbiased stereological computerised tomography (CT) method for estimating total human body (HB), skeletal muscle (SM) and adipose tissue (AT) volumes in groups of neuromuscular patients. In 10 neuromuscular patients HB, SM and AT volumes were estimated using systematic sampling on equidistant CT sections throughout the total body axis using a counting grid with systematically ordered intersection points. Each intersection point hitting HB, SM or AT represented a known volume dependent on intersection point distance and sum of section thickness and gap. Random and systematic intra- and interobserver errors for volume estimates were below 0.035. These errors were negligible to the coefficient of variation of the group mean, being 0.190 for HB, 0.323 for SM and 0.471 for AT. Even in the presence of intrafascicular and intramuscular fat in neuromuscular patients, unbiased and reliable quantification of HB, SM and AT is possible.

Strength training and albuterol in facioscapulohumeral muscular dystrophy.

BACKGROUND: In animals and healthy volunteers beta2-adrenergic agonists increase muscle strength and mass, in particular when combined with strength training. In patients with facioscapulohumeral muscular dystrophy (FSHD) albuterol may exert anabolic effects. The authors evaluated the effect of strength training and albuterol on muscle strength and volume in FSHD. METHODS: Sixty-five patients were randomized to strength training of elbow flexors and ankle dorsiflexors or non-training. After 26 weeks albuterol (sustained-release, 8 mg BID) was added in a randomized, double-blind, placebo-controlled design. Primary outcome was maximum voluntary isometric strength (MVIC) at 52 weeks. Secondary outcomes comprised dynamic strength and muscle volume. RESULTS: Training and albuterol were well tolerated. Training of elbow flexors did not result in a significant effect on MVIC, but dynamic strength improved significantly. Elbow flexor MVIC strength increased significantly in albuterol vs placebo treated patients. Ankle dorsiflexor strength decreased in all groups. Eleven out of twelve non-trained muscles in the albuterol group showed a positive effect on MVIC compared to the placebo group (p < 0.05 in seven muscle groups). Muscle volume decreased in the placebo-treated, and increased in the albuterol-treated patients. No synergistic or antagonistic effects were observed between training and albuterol. CONCLUSIONS: In FSHD strength training and albuterol appear safe interventions with limited positive effect on muscle strength and volume. Consequences of prolonged use are presently unclear, which precludes routine prescription.

A locus on chromosome 15q for a dominantly inherited nemaline myopathy with core-like lesions.

Nemaline myopathy is a congenital neuromuscular disorder characterized by muscle weakness and the presence of nemaline rods. Five genes have now been associated with nemaline myopathy: alpha-tropomyosin-3 (TPM3), alpha-actin (ACTA1), nebulin (NEB), beta-tropomysin (TPM2) and troponin T (TNNT1). In addition, mutations in the ryanodine receptor gene (RYR1) have been associated with core-rod myopathy. Here we report linkage in two unrelated families, with a variant of nemaline myopathy, with associated core-like lesions. The clinical phenotype consists of muscle weakness in addition to a peculiar kind of muscle slowness. A genome-wide scan revealed a locus for nemaline myopathy with core-like lesions on chromosome 15q21-q23 for both families. Combining the two families gave a two-point LOD score of 10.65 for D15S993. The alpha-tropomyosin-1 gene (TPM1) located within this region is the strongest candidate gene. However, no mutations were found in the protein-coding region of TPM1, although small deletions or mutations in an intron cannot be excluded. The critical region contains few other candidate genes coding for muscle proteins and several genes of unknown function, and has not yet been sequenced completely. The novel phenotype of nemaline myopathy in the two presented families corresponds to an also novel, as yet uncharacterized, genotype.

Mimic syndromes in sporadic cases of progressive spinal muscular atrophy.

Described are patients initially diagnosed with progressive spinal muscular atrophy (PSMA), in whom further evaluation established another diagnosis. The authors prospectively investigated incident and prevalent cases of PSMA. Seventeen of 89 patients, after initial registration, were later excluded because reassessment revealed a diagnosis other than PSMA. In 11 of the 17 patients with a revised diagnosis, a potential treatment was available: multifocal motor neuropathy (7), chronic inflammatory demyelinating polyneuropathy (2), inflammatory myopathy (1), and MG (1). Other misdiagnoses included myopathy, syringomyelia, ALS, idiopathic chronic axonal polyneuropathy, and idiopathic brachial plexus neuropathy. One patient with a possible herniated lumbar disk recovered spontaneously.

A new phenotype of autosomal dominant nemaline myopathy.

We present a five-generation family with a novel phenotype of autosomal dominant nemaline myopathy not linked to the three genes known to be causative for nemaline myopathy (alpha-tropomyosin-3, nebulin, and alpha-actin). Although there was muscle weakness in the neck flexors and proximal muscles of the limbs, as found in other families, facial, ankle dorsiflexor and respiratory muscles were normal. The most remarkable clinical feature was a peculiar kind of slowness in movement not reported previously in nemaline myopathy.

Evaluation of the traumatic coma data bank computed tomography classification for severe head injury.

This study determines the interrater and intrarater reliability of the Traumatic Coma Data Bank (TCDB) computed tomography (CT) scan classification for severe head injury. This classification grades the severity of the injury as follows: I = normal, II = diffuse injury, III = diffuse injury with swelling, IV = diffuse injury with shift, V = mass lesion surgically evacuated, or VI = mass lesion not operated. Patients with severe closed head injury were included. Outcome was assessed using the Glasgow Outcome Score (GOS) at 3 and 6 months. Four observers, two of them classifying the scans twice, independently evaluated CT scans. Of the initial CT scans of 63 patients (36 males, 27 females; age, 34+/-24 years), 6.3% were class I, 26.9% class II, 28.6% class III, 6.3% class IV, 22.2% were class V, and 9.6% class VI. The overall interrater and intrarater reliability was 0.80 and 0.85, respectively. Separate analyses resulted in higher inter- and intrarater reliabilities for the mass lesion categories (V and VI), 0.94 and 0.91, respectively, than the diffuse categories (I-IV) 0.71 and 0.67. Merging category III with IV, and V with VI resulted in inter- and intrarater reliabilities of 0.93 and 0.78, respectively. Glasgow outcome scores after 6 months were as follows: 19 dead (30%), one vegetative (2%), five severely disabled (8%), 17 moderately disabled (27%), and 21 good recovery (33%). Association measures (Sommers' D) between CT and GOS scores were statistically significant for all observers. This study shows a high intra- and interobserver agreement in the assessment of CT scan abnormalities and confirms the predictive power on outcome when the TCDB classification is used.

Homozygous deletion of the survival motor neuron 2 gene is a prognostic factor in sporadic ALS.

BACKGROUND: Spinal muscular atrophy (SMA) results from mutations of the survival motor neuron (SMN) gene on chromosome 5. The SMN gene exists in two highly homologous copies, telomeric (SMN1) and centromeric (SMN2). SMA is caused by mutations in SMN1 but not SMN2. The clinical phenotype of SMA appears to be related to the expression of SMN2. Patients suffering from the milder forms of SMA carry more copies of the SMN2 gene compared with patients with more severe SMA. It is suggested that the SMN2 gene is translated into an at least partially functional protein that protects against loss of motor neurons. OBJECTIVE: To investigate whether genetic mechanisms implicated in motor neuron death in SMA have a role in ALS. METHODS: The presence of deletions of exons 7 and 8 of SMN1 and SMN2 was determined in 110 patients with sporadic ALS and compared with 100 unaffected controls. RESULTS: The presence of a homozygous SMN2 deletion was overrepresented in patients with ALS compared with controls (16% versus 4%; OR, 4.4; 95% CI, 1.4 to 13.5). Patients with a homozygous SMN2 deletion had a shorter median time of survival (p < 0.009). Furthermore, multivariate regression analysis showed that the presence of an SMN2 deletion was independently associated with survival time (p < 0.02). No homozygous deletions in SMN1 were found. Carrier status of SMA appeared to be equally present in patients and controls (1 in 20). CONCLUSION: These results indicate that, similar to SMA, the SMN2 gene can act as a prognostic factor and may therefore be a phenotypic modifier in sporadic ALS. Increasing the expression of the SMN2 gene may provide a strategy for treatment of motor neuron disease.

Decreased striatal dopamine D2 receptor binding in amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA): D2 receptor down-regulation versus striatal cell degeneration.

Recently, decreased striatal dopamine D2-receptor binding was demonstrated in vivo in amyotrophic lateral sclerosis (ALS). To further elucidate the pathogenetic mechanism underlying this D2-receptor deficit, a multi-level comparison was made between 30 sporadic ALS subjects and 24 patients with multiple system atrophy (MSA), a disorder clinically characterized by bradykinesia, neuroradiologically by severe D2-receptor loss, and neuropathologically by degenerating striatal cells. The extent of D2-deficit in ALS and MSA were within the same range, but extrapyramidal signs and symptoms were virtually absent in our ALS patients. Striatal cell loss in general or competitive D2-receptor occupancy could be considered unlikely in ALS. The striatum receives massive glutamatergic input and the pathogenesis of ALS may be related to increased glutamatergic excitotoxicity. As other mechanisms (cell loss, receptor occupancy) could be ruled out, and as animal studies suggest that (excess of) glutamate decreases striatal D2-receptor synthesis, the striatal D2-receptor deficit in ALS is most likely to be caused by a receptor down-regulation.

Decreased striatal dopamine-receptor binding in sporadic ALS: glutamate hyperactivity?

The pathogenesis of ALS may be related to increased glutamatergic excitotoxicity. The striatum receives massive glutamatergic input. Animal studies suggest that glutamate decreases striatal D2-receptor synthesis. In drug-naive, sporadic ALS patients we demonstrated decreased striatal D2-receptor binding in vivo that could be partially reversed by the glutamatergic transmission blocker riluzole. Our findings support the glutamatergic excitotoxicity hypothesis in sporadic ALS.

MRI in patients with suspected vascular parkinsonism.

To determine whether MRI can reveal more vascular lesions in patients clinically suspected of having vascular parkinsonism, we compared 15 such patients with 15 patients who had idiopathic Parkinson's disease and 10 hypertensive controls. Patients with suspected vascular parkinsonism had significantly more subcortical lesions than those with Parkinson's disease or hypertension. The cutoff point that best distinguished patients with suspected vascular parkinsonism from patients with Parkinson's disease was a 0.6% level of lesioned brain tissue volume. There were two types of vascular parkinsonism: one had an acute onset and lesions located in the subcortical gray nuclei (striatum, globus pallidus, thalamus); the other had an insidious onset and lesions diffusely distributed in the watershed areas.

Immunological alterations induced by adjuvant treatment of postoperative colon carcinoma Duke's B or C with levamisole in combination with 5-FU.

BACKGROUND: Postoperative 5-FU combined with levamisole increases 5 year survival in colon cancer patients (Duke C) by 30% (1). In order to investigate the potential immunological mechanism, we determined lymphocyte subtypes and markers of immune activation in 22 patients before and during one year of postoperative adjuvant treatment. METHODS: Before and regularly during treatment, according to the scheme described by Moertel (1), major lymphocyte subsets were quantified by flow cytometry. Serum neopterin, soluble IL2-receptors, beta 2-microglobulin, TNF-alpha and interferon-gamma were determined by Elisa. RESULTS: The CD4/CD8 ratio increased significantly after levamisole was added to the treatment, as did the levels of soluble IL2-receptors. The percentages of T-cells expressing the interleukin 2 receptor followed a similar trend. The levels of neopterin tended to decrease during the combined treatment course. This was paralleled by a progressive fall in the proportion of T-cells expressing HLA-DR. CONCLUSIONS: The treatment induced significant and consistent alterations in major immunological mediators and lymphocyte subtypes. It remains to be established whether these changes are related to the therapeutic effect.